Non-Vitamin K Antagonist Oral Anticoagulants and Angioedema: A Cohort and Case-Crossover Study

Introduction Patients taking non-vitamin K antagonist oral anticoagulants (NOACs) such as dabigatran, rivaroxaban, and apixaban have reported experiencing angioedema in randomized trials and routine care. Objective The aim of this study was to quantify the association between NOACs and angioedema relative to warfarin among routinely treated patients with atrial fibrillation in a cohort study. We also compared warfarin users with non-users in a case-crossover study. Methods We utilized a cohort design that drew eligible patients from the Truven Health MarketScan Commercial database, the Optum© Clinformatics® Data Mart, and Medicare. Within each database, we compared the 6-month relative rate of angioedema among new users of NOACs (dabigatran, rivaroxaban, apixaban) and new users of warfarin. We estimated hazard ratios (HRs) and 95% confidence intervals (CIs) after adjusting for confounders using propensity score stratification, and meta-analyzed the database-specific HRs using a random-effects model. We also estimated an odds ratio (OR) for the association between warfarin and angioedema using a case-crossover design, a self-controlled design that controls for time-invariant confounders. Results In the cohort study, we observed 249 incident angioedema events among 267,681 NOAC initiators and 281,143 warfarin initiators across all databases. The meta-analyzed HR for angioedema comparing any NOAC versus warfarin was 0.98 (95% CI 0.76–1.27). In the case-crossover design, the OR for the association between warfarin and angioedema was 0.91 (95% CI 0.68–1.21) based on 431 cases. Conclusions Our estimates were inconsistent with substantial short-term relative increases in the rate of angioedema associated with oral anticoagulant therapy.